title: Hax-1: a regulator of calcium signaling and apoptosis progression with multiple roles in human disease.
abstract: BACKGROUND
  Hax-1, the hematopoietic cell-specific protein-associated protein X-1, is an inhibitor of apoptosis, which has been implicated in severe congenital neutropenia (SCN), neurological disorders and cancer. Hax-1 over-expression, as found in numerous types of cancer, results in resistance to granzyme B and caspase-3 and stabilizes the X-linked inhibitor of apoptosis, whereas its absence or knockdown promotes apoptosis. Hax-1 is bound to the cytosolic faces of mitochondria and the endoplasmic reticulum (ER). Interestingly, numerous viral proteins, including the classical swine fever virus N-terminal protease (N(pro)) and human immunodeficiency virus Vpr, interact with Hax-1 and disrupt its normal localization pattern. Recent findings have demonstrated that the localization to the ER allows Hax-1 to modulate calcium signaling via interactions with polycystin-2 and sarco(endo)plasmic reticulum calcium transport ATPase 2 (SERCA2).
  
  
  METHODS
  This review discusses how the interaction of Hax-1 with calcium-handling proteins could dominate over its other roles in apoptosis, since Hax-1 no longer blocks apoptosis on over-expression of SERCA2.
  
  
  CONCLUSIONS
  To facilitate pharmacological interference with the apoptosis-regulating functions of this protein, a better understanding of the Hax-1 intracellular targeting and protein-protein interactions is needed. Such an improved understanding would allow the generation of small molecule inhibitors that interfere with apoptosis-modulating functions of Hax-1 as seen in SCN.
authors.affiliation: University of Alberta, Department of Cell Biology, Medical Sciences Building, Room 5-65, Edmonton, Alberta, T6G 2H7 Canada. Thomas.Simmen@ualberta.ca
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020013:Calcium Signaling; D000080984:Congenital Bone Marrow Failure Syndromes; D016503:Drug Delivery Systems; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D009503:Neutropenia / Q000151:congenital / Q000188:drug therapy / Q000503:physiopathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C104759:HAX1 protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human